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213433Orig1s000 PRODUCT QUALITY REVIEW(S) CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 213433Orig1s000 PRODUCT QUALITY REVIEW(S) 5(&200(1'$7,21 ܈ $SSURYDO տ $SSURYDO ZLWK 3RVW0DUNHWLQJ &RPPLWPHQW տ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eference ID: 4654387 5HVSRQVH WR ,QIRUPDWLRQ &OLQLFDO 5HTXHVW &OLQLFDO 5HVSRQVH WR ,QIRUPDWLRQ 21'3 5HTXHVW 4XDOLW\ 5HVSRQVH WR ,QIRUPDWLRQ 21'3 5HTXHVW 4XDOLW\ 5HVSRQVH WR ,QIRUPDWLRQ 21'3 %LRSKDUP 5HTXHVW 4XDOLW\ 5HVSRQVH WR ,QIRUPDWLRQ &OLQLFDO 5HTXHVW &OLQLFDO 5HVSRQVH WR ,QIRUPDWLRQ 21'3 5HTXHVW 4XDOLW\ 5HVSRQVH WR ,QIRUPDWLRQ &OLQLFDO 5HTXHVW &OLQLFDO 5HVSRQVH WR ,QIRUPDWLRQ 21'3 DQG 230$ 5HTXHVW 4XDOLW\ 5HVSRQVH WR ,QIRUPDWLRQ &OLQLFDO 5HTXHVW &OLQLFDO 5HVSRQVH WR ,QIRUPDWLRQ 21'3 DQG 230$ 5HTXHVW 4XDOLW\ 5HVSRQVH WR ,QIRUPDWLRQ &OLQLFDO 5HTXHVW &OLQLFDO 5HVSRQVH WR ,QIRUPDWLRQ &OLQLFDO 5HTXHVW &OLQLFDO 5HVSRQVH WR ,QIRUPDWLRQ 230$ 0LFURELRORJ\ 5HTXHVW 4XDOLW\ 0XOWLSOH &DWHJRULHV $OO /DEHOLQJ 48$/,7< $66(660(17 7($0 'LVFLSOLQH 3ULPDU\ $VVHVVPHQW 6HFRQGDU\ $VVHVVPHQW 'UXJ 6XEVWDQFH -HIIUH\ 0HGZLG 3K' 'RQQD &KULVWQHU 3K' 'UXJ 3URGXFW =KHQJIDQJ *H 3K' 0RR-KRQJ 5KHH 3K' 0DQXIDFWXULQJ $PLW .RNDWH 3K' <XELQJ 7DQJ 3K' 0LFURELRORJ\ -DVRQ *RG 3K' 'HQLVH 0LOOHU 3K' %LRSKDUPDFHXWLFV 6ZDSQD 3DPX 3K' 9LGXOD .ROKDWNDU 3K' 5HJXODWRU\ %XVLQHVV 0HOLQGD %DXHUOLHQ 06 3URFHVV 0DQDJHU $SSOLFDWLRQ 7HFKQLFDO +DPLG 6KDILHL 3K' /HDG /DERUDWRU\ 275 1$ 1$ (QYLURQPHQWDO 5DDQDQ %ORRP 3K' 0LFKDHO )XUQHVV 3K' Reference ID: 4654387 EXECUTIVE SUMMARY I. RECOMMENDATIONS AND CONCLUSION ON APPROVABILITY The applicant of this 505(b)(2) new drug application has provided sufficient CMC information to assure the identity, purity, strength, and quality of the drug substance (clascoterone) and the drug product, WINLEVI® (clascoterone) Cream, 1%. Labels/labeling issues have been satisfactorily addressed. The Office of Process and Facility has made an overall “Acceptable” recommendation regarding the facilities involved in this NDA. The claim for categorical exclusion from the preparation of environmental assessment has been granted. Therefore, from the OPQ perspective, this NDA is recommended for APPROVAL with expiration dating period of 36 months. II. SUMMARY OF QUALITY ASSESSMENTS A. Product Overview The applicant, Cassiopea SpA has submitted this 505(b)(1) new drug application for WINLEVI® (clascoterone) Cream, 1% for topical administration. WINLEVI® is indicated for the treatment of acne vulgaris in patients 12 years of age or older. The active ingredient clascoterone is an androgen receptor inhibitor formulated as a white to almost white cream for topical dermatological use. Clascoterone is a white to almost white powder which is practically insoluble in water. Each gram of cream of WINLEVI container 10 mg of clascoterone as the active ingredient and cetyl alcohol, mono and diglycerides, mineral oil, propylene glycol, vitamin E, edetate disodium, polysorbate 80, citric acid monohydrate, and purified water as the inactive ingredients. WINLEVI cream is packaged and supplied as 60g in an epoxy-lined aluminum blind-end tube with a polypropylene cap. This product should be stored at 2ºC – 8ºC (38ºF – 46ºF) during shelf-life storage. Patients are instructed to store this drug product at room temperature 20ºC – 25ºC (68ºF – 78ºF) while in use. WINLEVI should be used within one month OPQ-XOPQ-TEM-0001v06 Page 1 Effective Date: February 1, 2019 after opening. The unused product should be discarded 180 days after the date of dispensing. WINLEVI cream is intended for topical administration to cleaned and dried affected skin area as uniform thin layer twice daily, in the morning and in the evening. Proposed Treatment of acne vulgaris in patients 12 years of Indication(s) age or older including Intended Patient Population Duration of As prescribed Treatment Maximum Daily Dose As prescribed Alternative Methods N/A of Administration B. Quality Assessment Overview Drug Substance: Adequate The drug substance, clascoterone is an androgen receptor inhibitor with a good skin permeation. It binds weakly to the human androgen receptor, thus blocking the receptor and preventing downstream androgenetic gene activation. Clascoterone has been classified as a new molecular entity (NME) and is intended as the active ingredient of topical cream indicated for the treatment of acne vulgaris in patients 12 years of age or older. Clascoterone is a white or almost white powder. It is practically insoluble in water, slightly soluble in ether, and very soluble in methanol and ethanol. It presents different polymorphic forms and the polymorphic form (b) (b) (4) identified as Form (4)shows a melting range of ºC. It also has (b) (4) the specific optical rotation of (b) (4) Clascoterone (USAN) also identified throughout the application as Cortexolone-17α-propionate (INN) has the chemical name, [(8R,9S,10R,13S,14S,17R)-17-(2-hydroxyacetyl)-10,13-dimethyl-3-oxo­ 2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthren-17-yl] propanoate, a molecular formula of C24H34O5, a molecular weight of 402.5 g/mol, and the chemical structure below: OPQ-XOPQ-TEM-0001v06 Page 2 Effective Date: February 1, 2019 Clascoterone is manufactured in accordance to current Good Manufacturing Practices (cGMP) requirements by (b) (4) and is packaged in (b) (4) . It is tested and release against a specification that assures the identity, strength, purity, and quality of the drug substance at release and throughout its (b) (b) (4) assigned retest date of (4) months when stored in a Information regarding the manufacture of clascoterone supplied by (b) (4) is provided in DMF (b) (4) . This DMF was reviewed by the Drug Substance Reviewer, Dr. Jeffrey Medwid on December 18, 2019 and was found to be adequate. In summary, based on the review of the manufacturing information provided in DMF (b) (4) and the review of the additional information provided in the Drug Substance Module of this application, Dr. Medwid has concluded that the drug substance information provided is adequate to support approval of this application from the drug substance perspective. Dr. Medwid’s review is provided in the Drug Substance Chapter of the Integrated Quality Assessment (IQA). Drug Product: Adequate WINLEVI® (clascoterone) Cream, 1% for topical administration has been developed for the treatment of acne vulgaris in patients 12 years of age or older. It is intended for twice a day topical application as uniform thin layer to cleaned dried affected skin area. WINLEVI has been formulated as a white to almost white (b) (4) cream. Each gram of the cream contains 10mg (1%) clascoterone as the active ingredient and cetyl alcohol, mono and diglycerides, mineral oil, propylene glycol, vitamin E, edetate disodium, polysorbate 80, citric acid monohydrate, and purified water as inactive ingredients. Inactive ingredients used in the composition of the drug product are all compendial materials. Clascoterone was found to be (b) (4) Therefore, the pH of final cream formulation was adjusted to (b) (4) for the Phase 3 studies. (b) (4) storage condition of 5ºC+ 3ºC was used and recommended as the shelf-life storage condition for the commercial drug product. OPQ-XOPQ-TEM-0001v06 Page 3 Effective Date: February 1, 2019 WINLEVI cream is manufactured in accordance to cGMP requirements by Cassiopea SpA and is packaged as 60g in epoxy-lined blind-end aluminum tubes with polypropylene caps. The drug product is tested against a specification that assures the identity, strength, purity, and quality of the drug product at release and throughout its proposed shelf- life of 36 months. The applicant has provided sufficient stability data that supports the expiration dating period of 36 months for the drug product stored at 2ºC – 8ºC (38ºF – 46ºF). The applicant has also provided sufficient stability data that supports the storage of the drug product at room temperature, 20ºC – 25ºC (68ºF – 78ºF) while in use. The drug product module of this application has been reviewed by the Drug Product Reviewer, Dr. Zhengfang Ge. Dr. Ge has concluded that the information provided in the drug product module is adequate to support the approval of this application from the drug product perspective. Dr. Ge’s review is provided in the Drug Product Chapter of the IQA. Labeling: Adequate The CMC sections of the Prescribing Information (PI) as well as the immediate container and carton labels have been reviewed by the Drug Product Reviewer, Dr. Zhengfang Ge. Dr. Ge has found that the final PI as well as immediate container and carton labels submitted to the application have satisfactorily resolved all deficiencies noted in her Labeling Review #1, and therefore, she has recommended approval of this application from
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